In Vitro and In Vivo Activation of Astrocytes by Amyloid-β is Potentiated by Pro-Oxidant Agents

Abstract

Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease. Age is the main risk factor for sporadic AD, which is the most prevalent type. Amyloid-beta peptide (Abeta) neurotoxicity is the proposed first step in a cascade of deleterious events leading to AD pathology and dementia. Glial cells play an important role in these changes. Astrocytes provide vital support to neurons and modulate functional synapses. Therefore, the toxic effects of Abeta on astrocytes might promote neurodegenerative changes that lead to AD. Aging reduces astrocyte antioxidant defenses and induces oxidative stress. We studied the effects of Abeta(42) on cultures of human astrocytes in the presence or absence of the following pro-oxidant agents: buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, and FeSO(4), which liberates redox active iron. Pro-oxidant conditions potentiated Abeta toxicity, as shown by the generation of free radicals, inflammatory changes, and apoptosis. Similar treatments were assessed in rats in vivo. A combination of Abeta(40) and Abeta(42) or Abeta(42) alone was infused intracerebroventricularly for 4 weeks. Other animal groups were also infused with BSO and FeSO(4). A long-term analysis that ended 4 months later showed greater cognitive impairment in the Morris water maze task, which was induced by Abeta plus pro-oxidant agent treatments. Pro-oxidant agents also potentiated brain tissue pathology. This was demonstrated in histological studies that showed highly increased astrocyte reactivity in AD-vulnerable areas, Abeta deposits, and oxidative damage of AD-sensitive hippocampal neurons. To increase our understanding of AD, experimental models should be used that mimic age-related brain changes, in which age-related oxidative stress potentiates the effects of Abeta.

Ganoderma atrum polysaccharide attenuates oxidative stress induced by d-galactose in mouse brain

“…The brain, with high oxygen demand, and relatively deficient in anti-oxidative defense, is the most susceptible organ to oxidative damage. Studies with D-gal-lesioned mice have demonstrated that D-gal-induced oxidative stress is a potent inducer of apoptosis (García-Matas et al, 2010;Recuero et al, 2009;Ritchie, 2009). In the present study, we also found that D-gal induced an increase in ROS generation and lipid peroxidation, and concomitantly increase of apoptosis, further suggesting that there is a close relationship between oxidative stress and brain injury.…”

Oxidative Stress and β-Amyloid Protein in Alzheimer’s Disease

“…Apart from its effects on the endothelial cells, another mechanism by which oxidative stress disrupts BBB is by damaging the astrocytes. Oxidative stress is an important cause of both the activation of astrocyte and the Ab production (Garcia-Matas et al 2010;Matos et al 2008). Oxidative stress and damaged astrocytes may promote BBB disruption in AD because tight junctions within the BBB are also enveloped by astrocytic end feet.…”

Melatonin plus physical exercise are highly neuroprotective in the 3xTg-AD mouse

“…However, melatonin treatment at old age in Tg2576 mice did not afford protection against oxidative damage (Quinn et al 2005). Oxidative damage is a biochemical hallmark of AD and a possible link between aging and AD (Castellani et al, 2008;García-Matas et al, 2010). Oxidative-stress-related derangements of neurotransmission and general brain function in aging and AD could be prevented or delayed by physical exercise and/or melatonin or other potent antioxidants and enhancers of antioxidant cell defenses.…”